Risk factors and causes of early death among patients with germ cell testis tumors (GCTs): An international collaborative study supported by the Global Society of Rare Genitourinary Tumors.

5030 Background: GCTs are the most common solid tumor in young men aged 20 to 40 years and are curable in most cases. However, a small proportion of patients with very advanced or aggressive disease, die early after starting chemotherapy. These patients are often not included in clinical trials and therefore accurate data on their risk factors and causes of death are critically lacking. Methods: This retrospective cohort study included patients with GCTs who died within 3 months from the completion of first-line systemic chemotherapy. Anonymized patients were included in an international database from tertiary cancer centers. Inclusion criteria were age ≥18 years, diagnosis between 2000-2024, death within 3 months from the last cycle of first-line chemotherapy, and treatment with systemic anticancer therapy and/or intention to treat. The database included data on patient and tumor characteristics, treatment and outcomes. Results: We identified 94 patients who experienced early death. Majority had IGCCCG poor prognosis and 16 (17%) had extragonadal GCTs. The proportion of these patients ranged from 0.4% to 2.1% of all patients treated with first line chemotherapy. Median time from starting of platinum based-therapy to death was 32 days (range: 2-301 days). Initial chemotherapy dose was reduced in 44.3% of patients. The most common causes of death were acute respiratory failure (ARF) due to acute respiratory distress syndrome (35.1%), disease progression (18.1%), febrile neutropenia (FN) with septic shock (13.8%), fatal extrapulmonary hemorrhage (13.8%), venous thromboembolism and myocardial infarction, each with an incidence of 2.1%. Approximately 11.7% of patients died from other causes and in 3.2% of cases the cause of death remains unknown. Factors associated with ARF development were older age (median age 43 years), lung involvement >50%, resting dyspnea and hemoptysis, but not choriocarcinoma histology, and less likely received bleomycin and/or initial dose reduction. Death within 30 days from starting chemotherapy (n=47, 50.0%) was associated with liver metastases, lung involvement >50%, beta-HCG > 50,000 mIU/mL, ECOG performance status 2-3, higher neutrophil/lymphocyte ratio and intensive or ventilated care (all p<0.05). Beyond ARF, fatal extrapulmonary hemorrhage (19.6%) and FN with septic shock (17.4%) were the most common cause of death within 30 days of starting therapy, while disease progression (29%) was more common in patients who died later. Conclusions: The proportion of patients with early death is low, but this group presents significant clinical challenges. Among advanced GCTs, high beta-HCG levels, liver metastases, massive lung involvement, poor ECOG and/or need of intensive care are associated with a higher risk of early death and need targeted intervention to improve their therapeutic outcomes.